The goal of this project is to characterize pituitary thyroid hormone resistance clinically, functionally and structurally. Resistance to thyroid hormone is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). Patients with generalized resistance (GRTH) display inappropriate secretion of thyrotropin (TSH) from the anterior pituitary and abnormal peripheral tissue response to thyroid hormone. These patients require higher levels of a thyroid hormone in order to suppress their TSHs into the normal range. Because the quantity of thyroid hormone required to overcome the resistance peripherally is the same, these patients are usually euthyroid. Diagnosis is suspected when the patient's TSHs prove normal or elevated despite elevated thyroid hormone levels. Selective pituitary resistance to thyroid hormone (PRTH) results in inappropriate TSH secretion in conjunction with peripheral tissue sensitivity to elevated thyroid hormone levels. These patients suffer hyperthyroid symptoms in a setting of elevated serum thyroid hormone levels and normal or elevated TSH levels. We previously reported a novel mutation of TR that selectively abolished thyroid receptor homodimer formation and results in PRTH in an affected individual. This report proved the first comprehensive clinical description of a patient with PRTH in conjunction with clear functional and structural associations. Although GRTH is well characterized, there has never been an exhaustive evaluation confirming PRTH as a distinct entity and describing it either clinically or biochemically. Such an evaluation would provide valuable clinical data from which clinicians could learn to recognize and correctly treat the disorder. Further, the advanced state of thyroid hormone receptor research allows it to serve as a paradigm of ligand-receptor-DNA interactions in general. Numerous disorders including diabetes mellitus and obesity are potential candidates for a resistance syndrome model with potential mutations yet to be determined. In a more general sense, the contribution to DNA regulation research from thyroid hormone receptor research is dramatic. My studies would expand these lessons in the groundbreaking direction of tissue specific receptor activity. Major objectives would be to identify patients with PRTH by rigorous clinical evaluation, to isolate the underlying receptor mutations, and to analyze the biochemical consequence of the mutations in order to define the roles of the effected domains.